1-phenyl-4-benzylpiperazines dopamine receptor subtype specific ligands

Abstract

Disclosed are compounds of the formula: or the pharmaceutically acceptable addition salts thereof wherein: R 1 is halogen or C 1 –C 4 alkyl; and R 2 and R 3 are the same or different and represent hydrogen, halogen, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, alkylthio, hydroxy, amino, mono(C 1 –C 4 )alkylamino, di(C 1 –C 4 )alkylamino, or R 2 and R 3 together represent a 4 carbon alkenylene moiety that together with the phenyl ring to which they are attached form a naphthyl moiety, which compounds are useful in the treatment of neuropsycological diseases such as schizophrenia, psychotic depression and mania.

1. A composition comprising a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable acid salt thereof, and a pharmaceutically acceptable excipient, wherein:
 R 1  is halogen or C 1 –C 4  alkyl; 
 R 2  represents halogen, C 1 –C 4  alkyl, C 1 –C 4  alkoxy, C 1 –C 4  alkylthio, hydroxy, amino, mono C 1 –C 4  alkylamino or di C 1 –C 4  alkylamino, 
 R 3  represesents hydrogen, halogen, C 1 –C 4  alkyl, C 1 –C 4  alkoxy, C 1 –C 4  alkylthio, hydroxy, amino, mono C 1 –C 4  alkylamino or di C 1 –C 4  alkylamino,
 with the proviso that R 2  and R 3  may not be 2-isopropoxyl and hydrogen respectively when R 1  is bromo. 
 
 
     
     
       2. A composition according to  claim 1 , wherein R 1  is methyl. 
     
     
       3. A composition comprising a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein
 R x  is fluorine, chlorine, bromine, or iodine; and 
 R 2  and R 3  are the same or different and represent hydrogen, halogen, C 1 –C 4  alkyl, C 1 –C 4  alkoxy, C 1 –C 4  alkylthio, hydroxy, amino, mono C 1 –C 4  alkylamino or di C 1 –C 4  alkylanino; 
 with the proviso that R 2  and R 3  may not be 2-isopropoxyl and hydrogen, respectively, when R x  is bromo. 
 
     
     
       4. A composition according to  claim 3 , wherein R x  is chloride; R 2  is chloride, methyl, ethoxy or methoxy; and R 3  is chloride, hydrogen or methyl. 
     
     
       5. A composition according to  claim 4 , wherein the phenyl group substituted with R 2  and R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       6. A composition comprising a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein
 R a  is C 1 –C 4  alkyl; and 
 R 2  represents halogen, C 1 –C 4  alkyl, C 1 –C 4  alkoxy, C 1 –C 4  alkylthio, hydroxy, amino, mono C 1 –C 4  alkylamino or di C 1 –C 4  alkylamino; 
 R 3  represents hydrogen, halogen, C 1 –C 4  alkyl, C 1 –C 4  alkoxy, C 1 –C 4  alkylthio, hydroxy, amino, mono C 1 –C 4  alkylamino or di C 1 –C 4  alkylamino. 
 
     
     
       7. A composition according to  claim 6 , wherein R a  is methyl. 
     
     
       8. A composition according to  claim 6 , wherein R 2  is chloride, fluoride, methyl or methoxy; and R 3  is hydrogen or methyl. 
     
     
       9. A composition according to  claim 7 , wherein the phenyl group substituted with R 2  and R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       10. A composition comprising a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein:
 R 1  is C 1 –C 4  alkyl or halogen. 
 
     
     
       11. A composition according to  claim 10 , wherein R 1  is chloro. 
     
     
       12. A composition according to  claim 1 , wherein the compound is selected from the group consisting of:
 1-(3-chlorophenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(2-chlorophenyi)-4-(4-chlorobenzyl)piperazine; 
 1-(3,4-dichiorophenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(4-methylphenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(3-methylphenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(2-methylphenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(3,4-dimethylphenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(4-methoxyphenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(3-methoxyphenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(2-methoxyphenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(4-ethoxyphenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(2-ethoxyphenyl)-4-(4-chlorobenzyl)piperazine; 
 1-(4chlorophenyl)-4-(4-fluorobenzyl)piperazine; 
 1-(4-chlorophenyl)-4-(4-methylbenzyl)piperazine; 
 1-(3-chlorophenyl)-4-(4-methylbenzyl)piperazine; 
 1-(3,4-dichioropheryl)-4-(4-methylbenzyl)piperazine; 
 1-(4-methylphenyl)-4-(4-methylbenzyl)piperazine; 
 1-(2-methylphenyl)-4-(4-methylbenzyl)piperazine; 
 1-(4-methoxyphenyl)-4-(4-methylbenzyl)piperazine; 
 1-(2-methoxyphenyl)-4-(4-methylbenzyl)piperazine; 
 1-(4-chlorophenyl)-4-(4-chlorobenzyl)piperazine; and 
 pharmaceutically acceptable salts thereof. 
 
     
     
       13. A composition according to  claim 3  wherein the compound is 1-phenyl-4-(4-chlorobenzyl)piperazine, or a pharmaceutically acceptable salt thereof.